Biological studies of dysthymia.

Dysthymic disorder (DD) is a chronic subsyndromal depressive condition that has generated increasing interest since its formal introduction into the psychiatric nomenclature in 1980. Although DD was included among the affective disorders in DSM-III, this classification was controversial. Some clinical and family studies support an association between DD and major depression disorder (MDD), but there has been little additional research firmly establishing the diagnostic validity of DD or clarifying its relation to MDD and to personality disorders. In this article, the literature on the biology of DD is reviewed. Studies of rapid eye movement (REM) latency, electrodermal activity, and the thyroid axis show similarities between DD and MDD, but the findings are mixed. Other investigations, including the Dexamethasone Suppression Test (DST), catecholamines, and several other electroencephalogram (EEG) sleep variables, show more consistent differences between DD and MDD. These findings suggest that DD manifests primarily trait characteristics of depression, thus differentiating it from the state characteristics of MDD. The methodological problems and implications of these studies, and suggestions for future research, are discussed.

Hypothalamic-pituitary-adrenocortical activity and response to cognitive behavior therapy in unmedicated, hospitalized depressed patients.

OBJECTIVE: Surprisingly little research supports the hypothesis that depressions characterized by objective measures of neurobiological dysregulation respond poorly to psychotherapy. Moreover, relevant studies testing this hypothesis have been compromised by low rates of neurobiological abnormality in outpatient samples. The authors therefore investigated response to cognitive behavior therapy in relation to pretreatment measures of hypothalamic-pituitary-adrenocortical (HPA) activity in hospitalized, yet unmedicated, patients. METHOD: The subjects were 29 unmedicated, hospitalized patients with major depression (DSM-III-R and Schedule for Affective Disorders and Schizophrenia/Research Diagnostic Criteria), nonpsychotic/nonbipolar subtype. After a 7- to 14-day evaluation, urinary free cortisol levels and dexamethasone suppression tests (DSTs) were obtained. Patients were treated for an average of 3 weeks with intensive individual cognitive behavior therapy. Response was assessed in relation to clinical severity of illness and pretreatment HPA parameters. RESULTS: Response to inpatient cognitive behavior therapy was inversely associated with pretreatment urinary free cortisol concentrations, although not strongly correlated with DST results. Overall, 12 (92%) of 13 cortisol suppressors on the DST who had normal urinary free cortisol concentrations responded to treatment, compared with only seven (44%) of the 16 patients characterized by nonsuppression of cortisol and/or elevated urinary free cortisol excretion. The relation between response to cognitive behavior therapy and HPA activity was not explained by clinical measures of symptom severity. CONCLUSIONS: Results are consistent with the hypothesis that patients with increased HPA function are less responsive to psychotherapy and, hence, might require somatic interventions. It is proposed that the negative impact of hypercortisolism on neurocognitive function mediates this relationship.

Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment.

BACKGROUND: Many studies of thyroid augmentation in refractory depression are methodologically weak, have had mixed results, and often do not include biological measures of hormonal effects. In this paper, recent clinical and preclinical research on thyroid dysfunction in refractory depression is reviewed. METHOD: A search of MEDLINE for articles published from 1970 to the present was conducted, in addition to a search of the bibliographies of published papers in this area. The clinical studies chosen for review included those in which the patient population was identified as having refractory depression and where a specific measure of thyroid function was used, such as thyroid indices, thyroid-releasing hormone stimulation, or basal metabolic rate. Animal studies of depression using the learned helplessness experimental paradigm were also reviewed and included if they examined the factors involved in antidepressant treatment response. RESULTS: Fifty-two percent of patients with refractory depression in six clinical studies evidenced subclinical hypothyroidism (range, 29%-100%), which can be contrasted with a prevalence of approximately 8% to 17% in unselected populations of depressed patients. Four studies investigating an animal model of refractory depression strongly implicate a pathophysiologic role for hypothyroidism, perhaps mediated by altered beta-adrenergic function. CONCLUSION: These findings indicate that hypothyroidism is significantly associated with refractory depression, suggesting that this characterizes one biological subtype of refractory depression. Failure to rigorously investigate the effects of thyroid augmentation, including measures of thyroid and beta-adrenergic function, may partly explain the ambiguous results from many treatment studies, and future research should incorporate these measures in the study of refractory depression.

Treating antidepressant nonresponders with augmentation strategies: an overview.

This paper provides an overview of antidepressant nonresponse and the role of augmentation strategies in the management of treatment-resistant depression. When effective, the more widely used augmentation strategies, including lithium salts, thyroid hormones, pindolol, buspirone, and psychostimulants, share two important advantages when compared with "switching" strategies: avoidance of ill effects associated with discontinuing the initial antidepressant and rapidity of onset of action. Ideally, advances in the understanding of the neurobiology of mood disorders and mechanisms of antidepressant response will permit a more efficient and specific matching between patient, initial antidepressant, and subsequent strategy for enhancing response to treatment.

Management of treatment-resistant depression: psychotherapeutic perspectives.

Treatment-resistant depression is a heterogeneous condition that occurs within a psychosocial milieu. The impact of prior pharmacologic interventions may have been adversely affected by a poor therapeutic alliance, low social support, life stress, or chronic adversity and cognitive or personality factors such as neuroticism or pessimism. This article considers the psychosocial factors that predispose to treatment-resistant depression and the psychotherapeutic principles thought to be helpful in both shorter- and longer-term treatment plans. We focus on the interpersonal, cognitive, and behavioral forms of treatment that constitute the depression-focused psychotherapies, which have been studied in major depressive disorder. Also discussed are modifications in treatment planning necessary to take into account the complexity of treatment-resistant depression.

Predictors of response to acute treatment of chronic and double depression with sertraline or imipramine.

BACKGROUND: The literature on predictors of response to treatment of nonchronic major depression has identified shorter duration of illness, acute onset, and less severity of illness as positive predictors. Unfortunately, there are almost no data on predictors of response to treatment for chronic depression. This study examined predictors of response to pharmacotherapy (sertraline or imipramine) in the treatment of outpatients who had DSM-III-R-defined chronic major or double depression. METHOD: The acute phase of the Chronic Major Depression and Double Depression Study is a double-blind, randomized, parallel-group 12-week comparison of sertraline and imipramine. Analyses are based on 623 patients who comprised the intent-to-treat sample, of whom 299 were nonresponders and 324 were responders, defined by a priori criteria as either remission or satisfactory therapeutic response. A stepwise logistic multiple regression analysis was performed on candidate clinical, psychosocial, and demographic variables previously identified as statistically significant in an attempt to develop a predictive model of positive antidepressant response. RESULTS: The sociodemographic variables that were predictive of positive response included living with spouse or partner or being at least a high school graduate. With regard to symptomatology and clinical history, responders had significantly lower baseline depression severity scores. In general, comorbid anxiety, substance abuse, and personality disorders did not influence rates of response. However, the presence of depressive personality traits was associated with a higher nonresponse rate. Among psychosocial variables, longer duration of personal relationships as well as higher baseline quality of life were associated with positive response. A stepwise logistic multiple regression identified 5 variables-living with spouse or partner, higher educational level, passive-aggressive personality, lower introverted-tense personality traits, and higher quality of life--that significantly and independently contributed to the predictive model. This model correctly classified 67% of patients. CONCLUSION: A higher baseline quality of life, living with spouse or partner, and having more education were the strongest predictors of response to acute pharmacotherapy among chronically depressed patients. Clinical variables and comorbidity were not identified as independent predictors, although personality traits did appear to influence treatment response. Overall, the predictive value of these baseline measures was modest, and therefore of limited clinical utility.

Comparison of DSM-III-R chronic major depression and major depression superimposed on dysthymia (double depression): validity of the distinction.

The nosology of chronic depression has become increasingly complex since the publication of the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R; American Psychiatric Association, 1987), but there are few data available to evaluate the validity of the distinctions between the subtypes of chronic depression. The validity of the distinction between DSM-III-R chronic major depression (CMD) and major depression superimposed on dysthymia (double depression, DD) was examined. Participants were 635 patients with chronic depression in a 12-week trial of antidepressant medications. Patients with CMD, DD, and a 3rd group with a chronic major depressive episode superimposed on dysthymia (DD/CMD) were compared on demographic and clinical characteristics, family history, and response to treatment. Few differences were evident, although the depression of patients with DD/CMD tended to be more severe.

Workplace performance effects from chronic depression and its treatment.

Utilizing data from a clinical trial and an econometric model incorporating the impact of a medical intervention and regression to the mean, we present evidence supporting the hypotheses that for chronically depressed individuals: (i) the level of perceived at-work performance is negatively related to the severity of depressive status; and (ii) a reduction in depressive severity improves the patient's perceived work performance. Improvement in work performance is rapid, with about two-thirds of the change occurring already by week 4. Those patients having the greatest work improvement are those with both relatively low baseline work performance and the least severity of baseline depression.

A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy.

The definitions that are commonly employed to describe the outcome of the depressive disorders are often used in inconsistent ways and remain largely untested. The lack of a standard and valid set of outcome definitions hinders the study of the naturalistic course and treatment of depressive disorders. In the present study, we operationalized definitions for response, remission, relapse, recovery, and recurrence and examined their validity in a sample of depressed patients treated with cognitive behavior therapy. Validity was evaluated by the ability of the definitions to predict subsequent outcome in acute treatment and during a 3 year follow-up period. All five definitions demonstrated moderate to excellent validity. Moreover, we were able to empirically distinguish response from remission, and relapse from recurrence, despite the frequent confusion of these terms in the literature. Several of the findings suggest that continued refinement of the outcome definitions may enhance validity even further.

Is cognitive behavior therapy just a 'nonspecific' intervention for depression? A retrospective comparison of consecutive cohorts treated with cognitive behavior therapy or supportive counseling and pill placebo.

BACKGROUND: There is a dearth of placebo-controlled studies of cognitive behavior therapy (CBT) of depression and the largest such study, by Elkin et al. (Arch. Gen. Psychiatry 46 (1989) 971-982), failed to find a significant difference between CBT and a clinical management plus placebo condition. METHODS: The outcomes of two consecutive cohorts of out-patients with major depressive disorder, treated with either CBT (n=90) or a nonspecific control condition (support-counseling-placebo; SCP: n=100), were compared. Although the principal comparisons between the CBT and SCP conditions were delimited to the first 4 weeks of treatment, a secondary set of analyses addressed the subset of 16 patients who received 12 additional weeks of supportive therapy. RESULTS: A consistent pattern of statistically and clinically significant differences favoring CBT over SCP was found in both weeks 4 and 16. LIMITATIONS: Interpretation of these findings are subject to several potential confounds, including the non-randomized nature of the groups and the greater amount of therapeutic contact during the first 4 weeks of CBT. CONCLUSIONS: While these results do not lessen the need for additional prospective studies, our findings do suggest that CBT has therapeutic effects beyond those attributable to placebo-expectancy and other nonspecific factors.

Early- versus late-onset dythymic disorder: comparison in out-patients with superimposed major depressive episodes.

BACKGROUND: This study examined the validity of the early-late onset subtyping distinction in dysthymic disorder. METHODS: Participants were 340 out-patients meeting DSM-III-R criteria for dysthymia and a concurrent major depressive episode (MDE). The sample was drawn from a 12-site double-blind randomized parallel group trial comparing the efficacy of sertraline and imipramine in the treatment of chronic depression. All patients received comprehensive evaluations using semi-structured interviews and rating scales. RESULTS: 73% of the sample met criteria for the early-onset, and 27% for the late-onset, subtype. The early-onset patients had a significantly longer index MDE, significantly higher rates of personality disorders and lifetime substance use disorders, and a significantly greater proportion had a family history of mood disorder. The subgroups did not differ in symptom severity or functional impairment at baseline, nor in response to a 12-week trial of antidepressants. LIMITATIONS: Further work is needed to extend these findings to dysthymic disorder without superimposed MDEs. CONCLUSIONS: These results support the distinction between early-onset and late-onset dysthymic disorder.

Dysthymia: clinical picture, extent of overlap with chronic fatigue syndrome, neuropharmacological considerations, and new therapeutic vistas.

Dysthymia, as defined in the American Psychiatric Association and International Classification of Mental Disorders, refers to a prevalent form of subthreshold depressive pathology with gloominess, anhedonia, low drive and energy, low self-esteem and pessimistic outlook. Although comorbidity with panic, social phobic, and alcohol use disorders has been described, the most significant association is with major depressive episodes. Family history is loaded with affective, including bipolar, disorders. The latter finding explains why dysthymia, especially when onset is in childhood, can lead to hypomanic switches, both spontaneously and upon pharmacologic challenge in as many as 30%. Indeed, antidepressants from different classes -tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase A (RIMAs), selective serotonin-reuptake inhibitors (SSRIs) and, more recently, amisulpride, and spanning noradrenergic, serotonergic as well as dopaminergic mechanisms of action - have been shown to be effective against dysthymia in an average of 65% of cases. This is a promising development because social and characterologic disturbances so pervasive in dysthymia often, though not always, recede with continued pharmacotherapy beyond acute treatment. Despite symptomatic overlap of dysthymia with chronic fatigue syndrome - especially with respect to the cluster of symptoms consisting of low drive, lethargy, lassitude and poor concentration - neither the psychopathologic status, nor the pharmacologic response profile of the latter syndrome is presently understood. Chronic fatigue today is where dysthymia was two decades ago. We submit that the basic science - clinical paradigm that has proven so successful in dysthymia could, before too long, crack down the conundrum of chronic fatigue as well. At a more practical level, we raise the possibility that a subgroup within the chronic fatigue group represents a variant of dysthymia.

Age of onset in chronic major depression: relation to demographic and clinical variables, family history, and treatment response.

BACKGROUND: The clinical and etiological significance of the early-late onset distinction in chronic major depressive disorder was explored. METHOD: Subjects were 289 outpatients with DSM-III-R chronic major depression drawn from a multi-site study comparing the efficacy of sertraline and imipramine in the acute and long-term treatment of chronic depression. Patients received comprehensive evaluations using semi-structured interviews and rating scales. RESULTS: Early-onset chronic major depression was associated with a longer index major depressive episode and higher rates of recurrent major depressive episodes, comorbid personality disorders, lifetime substance use disorders, depressive personality traits, and a history of psychiatric hospitalization. In addition, more early-onset patients tended to have a family history of mood disorders. The early-late onset distinction was not associated with differences in symptom severity, functional impairment, or treatment response. LIMITATIONS: Family members were not interviewed directly; there were a large number of statistical comparisons; and interrater reliability of the assessments was not evaluated. CONCLUSIONS: Early-onset chronic major depression has a more malignant course and is associated with greater comorbidity than late-onset chronic major depression.

Sertraline versus imipramine to prevent relapse in chronic depression.

BACKGROUND: Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS: After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS: Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS: The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS: Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Factors associated with chronic depressive episodes: a preliminary report from the STAR-D project.

OBJECTIVE: To identify baseline sociodemographic and clinical factors associated with a current chronic major depressive episode (MDE). METHOD: Outpatients with major depressive disorder enrolled in 41 US primary or psychiatric care sites were divided into two groups based on self-report of current episode length (<24 or > or =24 months). Logistic regression models were used to identify factors associated with chronicity of current depressive episode. RESULTS: About 21.2% of 1380 subjects were in current, chronic MDEs. Older age, less education, lower income, no private insurance, unemployment, greater general medical illness burden, lower physical quality of life, concurrent generalized anxiety disorder, fewer prior episodes, and history of prior suicide attempts were all associated with chronic episodes. Blacks, Hispanics, and patients receiving care in primary as opposed to psychiatric care settings exhibited greater chronicity. CONCLUSION: Chronic depressive episodes are common and are associated with greater illness burden, comorbidity, socioeconomic disadvantage, and racial/ethnic minority status.